"The significance is that any cell that can be saved by treatment is
likely to function normally, since that cell isn't sick."

A new view of the underlying mechanisms of Parkinson's, Huntington's
and other neurodegenerative diseases may result in novel treatments for
them, researchers report.

Such disorders result from the premature death of nerve cells that appear
to function normally to the end and not degenerate progressively, as has
been thought, the investigators said.

"The significance of this work is that it completely reorients our understanding
of neurological degenerations," said senior study author Roderick McInnes,
professor of molecular and medical genetics and pediatrics at the University
of Toronto.

The findings may influence how scientists conduct experiments and interpret
their results in the field and hold "important implications for the treatment
as well," McInnes said.

Researchers have long known that the death of neurons, the nerve cells
that carry messages to and from the brain, is behind Alzheimer's, Parkinson's
and the sudden loss of motor function in patients suffering from amyotrophic
lateral sclerosis, or ALS, better known as Lou Gehrig's disease.

While this common thread of cell fatalities has been shown to run through
these and other neurodegenerative disorders, more detailed attempts to
understand the factors that unite them have stumbled over such obstacles
as their varying times of onset and clinical progression.

Study Indicates Cell Death Not Gradual, But Random

Might the neuronal loss in all of these diseases follow a common course?
Or is the demise in each as individualized as some of the symptoms? The
experimental evidence from the animal and cell culture studies of Parkinson's,
Huntington's and retinal degeneration support a common, "one-hit" model
of cell death in inherited neurodegenerative diseases.

The findings argue against the hypothesis that cell damage accumulates
until it reaches lethal proportions, indicating instead that the time of
death of any neuron is random.

"Our findings demonstrate that, for many neurological degenerations,
the basic premise underlying the study of these diseases was incorrect,"
McInnes said. "That premise, designated 'the cumulative damage' model,
is that the mutant neurons (in those neuronal degenerations which are genetic
in origin) are initially in good health, but that they accumulate damage
as the years go by. Eventually a critical amount of damage accumulates,
and the cell dies."

Instead, "we found that they are at a constant increased risk of death,
as soon as they are formed," McInnes said, adding that the treatment goal
would be to return the risk to normal, i.e., zero, or at least to reduce
it.

"The obvious implication for treatment is that, if the affected neurons
are alive, they can be saved by any effective treatment that would function
well for the life of the patient," McInnes said. "In the cumulative damage
model, the situation is quite different. In that case, you might apply
treatment to a cell, but if its degeneration has progressed too far, it
may never function normally again."

"These results are certain to stimulate much debate and experimentation,
aimed both at identifying common mechanisms of neurodegeneration and at
developing common ways of intervening in these tragic diseases," said Nathaniel
Heintz of the Howard Hughes Medical Institute at the Rockefeller University
in New York, who wrote an accompanying article in the British journal Nature.

While convinced of the strength of their data, the study authors conceded
their model "might still be incorrect."

Unless damaged, normal neurons live as long as the body they inhabit.
In neurodegenerative diseases, one region of the nervous system suffers
a progressive loss of these irreplaceable cells. As the fatality count
rises, patients begin to experience symptoms, such as the tremors characteristic
of Parkinson's.

"The one-hit model proposes that the mutant neurons in inherited neurological
degenerations are in general good health and function well, except for
one thing: They are at an increased risk of dying compared to normal adult
neurons (which generally don't die)," McInnes said.

"The increase in risk of death is constant throughout the life of the
individual, and the time at which death occurs is totally random. This
model therefore predicts that cells in the affected parts of the brains
of patients with these diseases will function well until the cells die.
In fact, in those situations where function has been studied, as in retinal
degenerations, that is exactly what has been found: If the cell is alive,
it is well."

Geoff Clarke of the University of Toronto, lead author of the study
published in Nature, generated mathematical equations predicting the speed
of neuronal death caused by accumulated damage.

"These equations allowed me to study neuronal death that had been observed
by other investigators," he said. "I found that their data weren't consistent
with the idea of increasing amounts of cellular damage. Instead, our analysis
demonstrated that neuronal cell death in neurodegenerative diseases occurs
randomly during the life of the patient."

Taking their findings into account, McInnes, Clarke and colleagues from
the Universities of Toronto and British Columbia devised the "mutant steady
state model" to explain nerve cell death in inherited neurodegenerative
diseases.

Mutant Gene Scenario

In this scenario, mutant genes confer a small but definite increase
in risk of sudden programmed cell death in a perfectly normal, healthy
cell, they said.

The picture of mutant neurons in neurological degenerations resembles
that of very high cholesterol levels in a healthy-looking, athletic adult,
the scientists said.

"He looks and feels well and to all appearance is fine. But he is at
an increased risk of random death, if his coronary artery suddenly obstructs,"
McInnes said.

"Our work indicates that the neurons that are still alive are functioning
well for years or decades and are not seriously damaged, but they are at
increased risk of suddenly dying," he said. "The significance is that any
cell that can be saved by treatment is likely to function normally, since
that cell isn't sick."

If the new theory holds up, researchers could target whatever mechanism
increases the risk of neuronal death caused by mutant genes.

"If we can identify what critical reactions in the neurons lead to the
increased risk of programmed cell death, then we can try to push them back
towards normal. This will be tough, but there are some candidate molecules
that scientists have been investigating," McInnes said. "And while we did
not specifically study all neurodegenerative diseases, we suspect that
these findings may also apply to others like ALS and Alzheimer's disease."

The scientists now want to determine whether the model applies to other
neurological degenerations and to identify the critical biochemical abnormalities
that put the neuron at risk of death.

"The ultimate aim is to identify the critical biochemical abnormalities
in each disease and to learn how to reverse these abnormalities, thus taking
the cell out of harm's way," McInnes said.

This may take years, he said.

"However, this model is a solid first step in a new direction, hopefully
the right direction," McInnes said. "Maybe we will be lucky and be able
to identify one or more of the critical reactions soon, and maybe some
of the critical reactions will be the same in different diseases."

The work was funded by the Foundation Fighting Blindness, The Macular
Vision Research Foundation, The RP Eye Research Foundation of Canada, the
Medical Research Council of Canada, the Canadian Genetic Disease Network
and the Huntington's Disease Society of America.